CD19-Directed CAR T-Cell Therapy Demonstrates Clinical Efficacy in Richter Transformation

Adam Kittai, MD

Several CD19-directed CAR T-cell therapies that are FDA approved for the treatment of patients with non-Hodgkin lymphoma demonstrated clinical efficacy in patients with Richter transformation, according to findings from a retrospective study published in the Journal of Clinical Oncology.

Patients with Richter transformation (n = 69) achieved a median progression-free survival (PFS) of 4.7 months (95% CI, 2.0-6.9) at a median follow-up of 24 months following CAR T-cell therapy infusion. The 1-year and 2-year PFS rates were 35.7% (95% CI, 24.3%-47.3%) and 28.9% (95% CI, 17.8%-40.8%), respectively. Additionally, patients achieved a median overall survival (OS) of 8.5 months (95% CI, 5.1-25.4) with 1- and 2-year OS rates of 42.9% (95% CI, 30.7%-54.4%) and 38.3% (95% CI, 26.2%-50.3%), respectively.

Among the 66 patients evaluable for response assessment—3 patients died prior to assessment due to adverse effects (AEs) following CAR T-cell therapy infusion—the overall response rate was 63% comprised of a 46% complete response (CR) rate and 17% partial response (PR) rate. The median duration of response was 27.6 months (95% CI, 14.5-not reached [NR]) among patients who achieved CR compared with 2.1 months (95% CI, 1.0-3.3) for those who achieved a PR. Further, 1 patient experienced stable disease and 30% of patients experienced disease progression, with progression occurring in the central nervous system in 3 patients.

The international, multicenter, retrospective study included patients with Richter transformation who received CAR T-cell therapy at 12 academic centers; patients received either axicabtagene ciloleucel (axi-cel; Yescarta; n = 44; 64%), tisagenlecleucel (tisa-cel; Kymriah; n = 17; 25%), lisocabtagene maraleucel (liso-cel; Breyanzi; n = 7; 10%), or brexucabtagene autoleucel (brexu-cel; Tecartus; n = 1; 1%). Richter transformation was defined as patients with large B-cell lymphoma (LBCL) with preceding or concurrently diagnosed chronic lymphocytic leukemia (CLL). Further, those with Hodgkin lymphoma or other subtypes of Richter transformation were not included in the study.

Patients included in the study were a median age of 56 years (range, 23-74) at CLL diagnosis, 63 years (range, 26-80) at Richter transformation diagnosis, and 64 years (range, 27-80) at CAR T-cell therapy infusion. Most patients were male (63.8%), received therapy for CLL prior to Richter transformation (82.6%), had IGHV-unmutated disease at CLL diagnosis (86.7%), and had a complex karyotype at Richter transformation diagnosis (65.5%). At CLL diagnosis, patients had a median of 3 (range, 0-20) karyotypic abnormalities.

Regarding cytogenetics at Richter transformation diagnosis, patients had a 17p deletion (n = 12/29) and complex karyotype (n = 19/29). Additionally, patients had TP53-mutated (n = 14/24), NOTCH1-mutated (n = 4/19), MYC translocated (n = 8/40), and/or MYC overexpressing (n = 29/52) disease. The median largest lymph node was 3.5 cm (range, 0.7-16.0) and patients received a median of 2 (range, 0-7) lines of therapy for Richter transformation; most patients (62.3%) also received prior treatment with a BTK inhibitor or BCL2 inhibitor for both CLL and Richter transformation.

Additional data revealed that the estimated nonrelapse mortality rates were 7.3% (95% CI, 2.7%-15.0%) at 3 months and 13.4% (95% CI, 6.5%-22.8%) at 12 months postinfusion. A post-treatment CLL minimal residual disease (MRD) assessment was also conducted in 27 patients, and among the 22 patients who had undetectable MRD in the blood or bone marrow, the median PFS was 20.3 months (6.6-NR), and the median OS was 38.4 months (8.6-NR).

“On multivariable analysis for PFS after CAR T infusion, higher baseline lactate dehydrogenase and c-reactive protein remained associated with shorter PFS,” Adam S. Kittai, MD, lead study author and associate professor of medicine (hematology and medical oncology) at Mount Sinai in New York, New York, and coauthors wrote in the publication. “On multivariable analysis for OS after CAR T-[cell therapy] infusion, a greater number of previous lines of therapy for Richter transformation, higher baseline tumor Ki67 proliferation index, and higher baseline LDH and CRP were associated with shorter OS.”

Regarding safety, notable grade 3 or higher AEs included cytokine release syndrome (16%), immune effector cell–associated neurotoxicity syndrome (ICANS; 37%), infection (20.3%), neutropenia (87.0%), and thrombocytopenia (71.0%). Febrile neutropenia also occurred in 66.7% of patients. Grade 3 or higher ICANS occurred in 43% of patients treated with axi-cel or brexu-cel and 25% of those treated with tisa-cel or liso-cel.

“This representative cohort demonstrates the feasibility and efficacy of [CAR T-cell] therapy for a very challenging-to-treat disease. Additional work is needed to optimize patient selection, bridging therapy, and post–CAR T maintenance therapy, to both enhance efficacy and reduce toxicity. As with CAR T-cell therapies in LBCL, infection remains the major cause of nonrelapse mortality and rigorous attention to anti-infective prophylaxis and measures to mitigate risks related to COVID-19 disease should be implemented. Our data support the continuous exploration of CAR T-cell therapy for Richter transformation through prospective clinical trials,” the study authors wrote.

Study authors also added that although lower CRs have been reported with CAR T-cell therapy in CLL, Richter transformation is immunologically distinct from CLL. That combined with the data from this retrospective study suggest that pretreated patients with Richter transformation may be able to achieve similar remission rates with CAR T-cell therapy as patients with LBCL.

Reference

Kittai AS, Bond D, Huang Y, et al. Anti-CD19 chimeric antigen receptor T-cell therapy for richter transformation: an international, multicenter, retrospective study. J Clin Oncol. 2024;42(17):2071-2079. doi:10.1200/JCO.24.00033